ABSTRACT Renal Cell Carcinoma (RCC) is the most common type of kidney cancer in adults. RCC is highly resistant to both chemotherapy and radiotherapy; and therapeutic benefits with immunotherapeutic strategies are not remarkable. Aberrant signaling through Receptor Tyrosine Kinases (RTKs) plays a major role in renal tumor growth. In both clear cell and papillary RCC, the RTK c-Met is hyperactive; and plays an important role in conferring resistance to targeted therapies. In our recent study, we have demonstrated that HGF/c-Met- mediated signaling activated Ras/Raf/PI3K pathway and down-regulated renal cancer cells apoptosis; and it was associated with the overexpression of cytoprotective heme oxygenase-1 (HO-1). We have also observed that siRNA-mediated silencing of HO-1 significantly decreased the c-Met-induced inhibition of renal cancer cell apoptosis. A small molecule c-Met inhibitor (Cabozantinib/XL-184) has recently been approved by the FDA for the treatment of advanced RCC. However, reports suggest that acquired drug resistance to c-Met inhibition through gene mutations and chromosome amplification, and dose-dependent toxicity are major hurdles in the use of Cabozantenib/XL-184; and can potentially subdue the anti-tumor effects of c-Met inhibitor therapy. Therefore, targeting c-Met along with its potent downstream effector molecule(s) can overcome the aforementioned hurdles. One such potential target can be Renalase (RNLS), a secreted flavoprotein from renal tissues in response to hypoxia and tissue injury. RNLS, through its amine oxidase function, modulates systemic blood pressure. Independent of its intrinsic enzymatic activity, recent reports suggest that RNLS and its receptor PMCA4b-mediated signaling activates MAPK and PI3K pathways to mediate cytoprotection; and it is markedly increased in tumor tissues and can serve as a prognostic marker. Kidney tissues are the predominant source of RNLS; yet, the role of RNLS in the growth and survival of renal cancer cells has not been studied. In our preliminary studies, we found that RNLS is overexpressed in renal cancer cells and HGF treatment further increased the expression of RNLS; and inhibition of c-Met (using XL-184) decreased the level of RNLS expression in these cells. We hypothesized that RNLS, in addition to promoting tumorigenic pathways independently, can also serve as one of the effector molecules for c-Met-induced growth of renal tumors. Thus, the over-expressed RNLS can significantly augment c-Met-mediated signaling axis to promote tumor growth. Through this proposal, we will bring-forth the pro-tumorigenic role of RNLS in RCC and identify the previously unrecognized role for c-Met activation in increasing the expression of RNLS in cancer cells. We will explore the efficacy of targeting both c-Met and RNLS in restricting renal tumor growth in vivo. We will generate significant data to support the potential therapeutic benefit of co-targeting c-MET and RNLS in restricting renal tumor growth; and this should have a major impact in the treatment of RCC.